scholarly journals Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells

2011 ◽  
Vol 188 (3) ◽  
pp. 1091-1097 ◽  
Author(s):  
Matthias Klein ◽  
Martin Vaeth ◽  
Tobias Scheel ◽  
Stephan Grabbe ◽  
Ria Baumgrass ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate

Downregulation of JAK3 Protein Levels in T Lymphocytes by Prostaglandin E2 and Other Cyclic Adenosine Monophosphate-Elevating Agents: Impact on Interleukin-2 Receptor Signaling Pathway

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2308-2318 ◽  
Author(s):  
Vladimir Kolenko ◽  
Patricia Rayman ◽  
Biswajit Roy ◽  
Martha K. Cathcart ◽  
John O’Shea ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Lymphocytes ◽  
Prostaglandin E2 ◽  
Signaling Pathway ◽  
Interleukin 2 ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Naïve T Cells ◽  
Dependent Signal

The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)–dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2(PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56lck, and p59fyn) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (γc) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2–dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2–dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.

scholarly journals Cyclic adenosine monophosphate is a key component of regulatory T cell–mediated suppression

2007 ◽  
Vol 204 (6) ◽  
pp. 1303-1310 ◽  
Author(s):  
Tobias Bopp ◽  
Christian Becker ◽  
Matthias Klein ◽  
Stefan Klein-Heßling ◽  
Alois Palmetshofer ◽  
...  
Keyword(s):  
T Cells ◽  
Gap Junctions ◽  
Gap Junction ◽  
Molecular Mechanisms ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Peripheral Tolerance ◽  
Cell Contact ◽  
Camp Content ◽  
Naturally Occurring

Naturally occurring regulatory T cells (T reg cells) are a thymus-derived subset of T cells, which are crucial for the maintenance of peripheral tolerance by controlling potentially autoreactive T cells. However, the underlying molecular mechanisms of this strictly cell contact–dependent process are still elusive. Here we show that naturally occurring T reg cells harbor high levels of cyclic adenosine monophosphate (cAMP). This second messenger is known to be a potent inhibitor of proliferation and interleukin 2 synthesis in T cells. Upon coactivation with naturally occurring T reg cells the cAMP content of responder T cells is also strongly increased. Furthermore, we demonstrate that naturally occurring T reg cells and conventional T cells communicate via cell contact–dependent gap junction formation. The suppressive activity of naturally occurring T reg cells is abolished by a cAMP antagonist as well as by a gap junction inhibitor, which blocks the cell contact–dependent transfer of cAMP to responder T cells. Accordingly, our results suggest that cAMP is crucial for naturally occurring T reg cell–mediated suppression and traverses membranes via gap junctions. Hence, naturally occurring T reg cells unexpectedly may control the immune regulatory network by a well-known mechanism based on the intercellular transport of cAMP via gap junctions.

Downregulation of JAK3 Protein Levels in T Lymphocytes by Prostaglandin E2 and Other Cyclic Adenosine Monophosphate-Elevating Agents: Impact on Interleukin-2 Receptor Signaling Pathway

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2308-2318 ◽  
Author(s):  
Vladimir Kolenko ◽  
Patricia Rayman ◽  
Biswajit Roy ◽  
Martha K. Cathcart ◽  
John O’Shea ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Lymphocytes ◽  
Prostaglandin E2 ◽  
Signaling Pathway ◽  
Interleukin 2 ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Naïve T Cells ◽  
Dependent Signal

Abstract The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)–dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2(PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56lck, and p59fyn) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (γc) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2–dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2–dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.

scholarly journals Cyclic adenosine monophosphate response to prostaglandin E2 on subpopulations of human lymphocytes.

1979 ◽  
Vol 150 (5) ◽  
pp. 1260-1264 ◽  
Author(s):  
J S Goodwin ◽  
P A Kaszubowski ◽  
R C Williams
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cyclic Amp ◽  
Prostaglandin E2 ◽  
Cell Population ◽  
Human Lymphocytes ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Prostaglandin Receptors ◽  
Fourfold Increase

Receptors for prostaglandin E2 or histamine were measured on subpopulations of human lymphocytes, using the cyclic AMP increase after exposure to prostaglandin or histamine as an indicator for the presence of receptors. The cyclic AMP response to prostaglandin E2 was similar in unfractionated lymphocytes and the T-enriched and T-depleted fractions. Within the T-enriched population, T cells bearing a receptor for the Fc portion of IgG (T gamma-cells) had a 27.4-fold rise in cyclic AMP after exposure to prostaglandin E2, whereas the remaining T cells (non-T gamma cells) had a fourfold increase. It would appear that prostaglandin receptors are concentrated on a small subfraction of T gamma cells, comprising approximately 15% of the T-cell population. The cyclic AMP response to histamine was less than twofold in all lymphocyte fractions.

Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1582-1589 ◽  
Author(s):  
Max Schnurr ◽  
Tracey Toy ◽  
Amanda Shin ◽  
Moritz Wagner ◽  
Jonathan Cebon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Interferon Γ ◽  
P2 Receptors ◽  
Interleukin 12 ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Ifn Γ

AbstractThe interleukin-12 (IL-12) cytokine family plays important roles in the orchestration of innate and adaptive immunity by dendritic cells (DCs). The regulation of IL-12 expression has been thoroughly studied, but little is known about factors governing the expression of IL-23 and IL-27, 2 novel IL-12 family members acting on memory and naive T cells, respectively. We report that the expression of these cytokines by DCs was critically dependent on the mode of activation. DC activation by CD40L predominantly induced IL-12. Ligands of the Toll-like receptor (TLR) 3 and TLR4 induced IL-12 and IL-27, whereas exposure to intact Escherichia coli resulted in high expression of IL-12, IL-27, and IL-23. The nucleotide adenosine triphosphate (ATP) has been shown to inhibit IL-12 production by P2 receptors. We found that ATP also inhibited IL-27 expression but enhanced IL-23 expression. Interestingly, the reciprocal regulation of IL-12/IL-27 and IL-23 by ATP was mediated by 2 distinct P2 receptors and was also induced by prostaglandin E2 by cyclic adenosine monophosphate (cAMP)–elevating EP2/EP4 receptors. As a consequence, DCs were selectively impaired in their ability to induce interferon-γ (IFN-γ) in naive T cells but continued to promote IFN-γ and IL-17 production in memory T cells. These studies identify P2 receptors as promising targets for the design of novel strategies to manipulate specific stages of T-cell responses and to treat IL-12– and IL-23–mediated disorders.

scholarly journals CD39 Regulation and Functions in T Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8068
Author(s):  
Eleonora Timperi ◽  
Vincenzo Barnaba
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Genetic Factors ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Preclinical Models ◽  
Cell Compartment

CD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer.

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